Radiohalogenated pyrimidine nucleosides have been shown to be useful in the diagnosis and treatment of tumors in mammals. For instance, a method of diagnosing tumors using radiohalogenated pyrimidine nucleosides, such as 5-(.sup.123 I)Iodo-2'deoxyuridine is described in U.S. Pat. No. 5,094,835 and U.S. Pat. No. 5,308,605, the disclosures of which are incorporated herein by reference. Such radiolabeled compounds can be used to follow the development of tumors. Additionally, tumors in mammals can be treated by injecting or infusing an effective amount of radiohalogenated pyrimidine nucleosides directly to the affected site (see U.S. Pat. No. 5,077,034, the disclosure of which is incorporated herein by reference).
5'-Iodo-2'-deoxyuridine (IUdR) is a thymidine (TdR) analog in which the 5-methyl group of TdR is replaced by iodine. Because the 5-methyl group and the iodine atom have similar van der Waals' radii, this substitution gives a compound that behaves remarkably like TdR and, thus, has been extensively studied. Within the cell, both TdR and IUdR are phosphorylated in a stepwise fashion and are incorporated into DNA. Previous studies have shown that this halogenated nucleotide sensitizes mammalian cells to the effects of radiation. When labeled with the Auger electron emitter .sup.123 I or .sup.125 I, radioiodinated IUdR exhibits substantial toxicity in mammalian cells in vitro (Hofer, K. G., et al., (1975) Int. J. Radiat. Biol. 28: 225-241; Chan, P. C., et al., (1976) Radiat. Res. 67: 332-343; Kassis, A. I., et al., (1987) Radiat. Res. 111: 305-318; Makrigiorgos, G. M., et al., (1989) Radiat. Res. 118: 532-544) and is highly therapeutic in several animal tumor models (Bloomer, W. D. and Adelstein, S. J. (1977) Nature 265: 620-621; Baranowska-Kortylewicz, J., et al., (1991) Int. J. Radiat. Oncol. Biol. Phys. 21: 1541-1551; Kassis, A. I., et al., (1993) J. Nucl. Med. 34: 241P). Furthermore, the locoregional (intratumoral, intrathecal, intraperitoneal, intravesical) administration of IUdR radiolabeled with the gamma emitter .sup.123 I or .sup.123 I is useful for scintigraphic detection of animal and human tumors (Kassis, A. I., (1990) J. Nucl. Med. Allied Sci. 34: 299-303; Kassis, A. I., (1990) Cancer Res. 50: 5199-5203; Baranowska-Kortylewicz, J., et al., (1991) supra; Van den Abbeele, A. D., et al., (1992) in Biophysical Aspects of Auger Processes, American Association of Physicists in Medicine Symposium Proceedings No 8 (Edited by Howell R. W., Narra V. R., Sastry K. S. R. and Rao D. V.) pp. 372-395, American Institute of Physics, Woodbury, N.Y.; Mariani, G., et al., (1993) J. Nucl. Med. 34: 1175-1183; Kassis, A. I., et al., (1994) Proc. Am. Assoc. Cancer Res. 35: 414). In addition, intravenously administered radiolabeled IUdR is used in the detection of actively growing regions within tumors (Tjuvajev, J. G., et al., (1994) J. Nucl. Med. 35: 1407-1417).
IUdR has certain characteristics which make radiolabeled IUdR useful for the treatment or diagnosis of tumors whether macroscopically observable or not. For instance, since IUdR is a low-molecular-weight molecule, it diffuses readily within tissues. When radiolabeled with an Auger electron emitter, e.g., .sup.123 I, .sup.125 I, .sup.77 Br, .sup.80m BR, IUdR is innocuous outside the cell and ineffective at killing cells when within the cytoplasm. It is, for the most part, taken up selectively by dividing cancerous cells located within nondividing cells and is indefinitely retained following DNA incorporation. Nondividing cells will not incorporate IUdR into their DNA and most of the IUdR that is not taken up by cancerous cells will be catabolized/dehalogenated rapidly [t.sub. 1/2 of min] and thus will not incorporate into the DNA of distant noncancerous dividing cells. Furthermore, since it is a small molecule, IUdR will not induce an antibody response and as such will lend itself to repeated injections/continuous infusion.
Previously described methods for synthesizing radiolabeled IUdR used a demercurization reaction from a suspension of 5-chloromercuri-2'-deoxyuridine (ClHgUdR) in water using sodium [.sup.123/125/131 I] iodine and Iodogen as the oxidant. The IUdR is isolated and, then, purified by HPLC (high performance liquid chromatography) due to the presence of contaminants, such as UdR, ClUdR and mercury. The entire process typically takes approximately 6 hours (Kassis and Baranowska-Kortylewicz, U.S. Pat. No. 4,851,520; Baranowska-Kortylewicz, J., et al., (1988) Appl. Radiat. Isot. 39: 335-341).
Recently, the preparation of radiolabeled IUdR by destannylation of 5-trimethylstannyl-2'-deoxyuridine ((CH.sub.3).sub.3 SnUdR) has also been described (Baranowska-Kortylewicz, J., et al., (1994) J. Labelled Cmpd. Radiopharm. 34: 513-521). The stannyl precursor is more stable than the mercurial precursor. The authors also claim in this publication that, as a consequence of the difference in solubility of the stannyl precursor and IUdR in aqueous solution, radiolabeled IUdR can be isolated by elution through a reverse-phase C.sub.18 cartridge. However, we have been unable to reproduce these reported results. In fact, IUdR cannot be synthesized from (CH.sub.3).sub.3 SnUdR precursor using the conditions prescribed in this publication. Furthermore, contrary to this publication, IUdR cannot be eluted from reverse planar C-18 adsorbants.
It can be appreciated that it is desirable to have a method for synthetic preparation of radiolabeled pyrimidine nucleosides or nucleotides that is rapid, efficient, and easily reproducible. It is further desirable that such a process produces radiolabeled nucleosides or nucleotides free of toxic contaminants and which therefore do not require further purification.